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Journal articles
Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2
Christopher Duncan
1, *
Benjamin Thompson
1
Rui Chen
1
Gillian Rice
2
Florian Gothe
1, 3
Dan Young
4
Simon Lovell
2
Victoria Shuttleworth
1
Vicky Brocklebank
1
Bronte Corner
1
Andrew Skelton
1
Vincent Bondet
5
Jonathan Coxhead
1
Darragh Duffy
5
Cécile Fourrage
6
John Livingston
7
Julija Pavaine
8, 2
Edmund Cheesman
8
Stephania Bitetti
8
Angela Grainger
1
Meghan Acres
1
Barbara Innes
1
Aneta Mikulasova
1
Ruyue Sun
1
Rafiqul Hussain
5
Ronnie Wright
2, 8
Robert Wynn
9
Mohammed Zarhrate
10
Leo Zeef
2
Katrina Wood
11
Stephen Hughes
9, 8
Claire Harris
1
Karin Engelhardt
1
Yanick Crow
10, 12, 13
Richard Randall
4
David Kavanagh
1, 11
Sophie Hambleton
1, 11, *
Tracy Briggs
2, 8, *
*
Corresponding author
Christopher Duncan 1
Correspondent author
Benjamin Thompson 1
Author
Rui Chen 1
Author
Gillian Rice 2
Author
Vicky Brocklebank 1
Author
Bronte Corner 1
Author
Andrew Skelton 1
Author
Vincent Bondet 5
Author IdHAL : vincent-bondet ORCID : https://orcid.org/0000-0002-6534-0984
Jonathan Coxhead 1
Author
Darragh Duffy 5
Author IdHAL : darragh-duffy ORCID : https://orcid.org/0000-0002-8875-2308
Cécile Fourrage 6
Author
John Livingston 7
Author
Julija Pavaine 8, 2
Author
Edmund Cheesman 8
Author
Stephania Bitetti 8
Author
Angela Grainger 1
Author
Karin Engelhardt 1
Author
Yanick Crow 10, 12, 13
Author IdHAL : yanick-crow ORCID : https://orcid.org/0000-0001-7211-7564
Richard Randall 4
Author
David Kavanagh 1, 11
Author
Sophie Hambleton 1, 11
Correspondent author
Tracy Briggs 2, 8
Correspondent author
1
Newcastle University [Newcastle] (Newcastle upon Tyne NE1 7RU - United Kingdom)
2
University of Manchester [Manchester] (Oxford Rd, Manchester M13 9PL - United Kingdom)
3
LMU - Ludwig-Maximilians-Universität München (Geschwister-Scholl-Platz 1, 80539 München - Germany)
4
University of St Andrews [Scotland] (St Andrews KY16 9AJ, Fife, Scotland, UK - United Kingdom)
5
Immunobiologie des Cellules dendritiques (Département d'Immunologie, 25-28 rue du Docteur Roux, 75724 Paris cedex 15 - )
- Institut Pasteur [Paris] (25-28, rue du docteur Roux, 75724 Paris cedex 15 - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U1223 (101, rue de Tolbiac, 75013 Paris - France)
6
Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU) (IHU Imagine,
156 rue de Vaugirard, 75015 PARIS
et
24 Boulevard du Montparnasse, 75015 Paris - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U1163 (101, rue de Tolbiac, 75013 Paris - France)
- UP - Université de Paris : UMR_S 1163 (85 boulevard Saint-Germain 75006 Paris - France)
7
University of Leeds (Woodhouse Lane, Leeds LS2 9JT - United Kingdom)
9
Royal Manchester Children's Hospital (United Kingdom)
- University of Manchester [Manchester] (Oxford Rd, Manchester M13 9PL - United Kingdom)
10
IMAGINE - U1163 - Imagine - Institut des maladies génétiques (IHU Imagine,
156 rue de Vaugirard, 75015 PARIS
et
24 Boulevard du Montparnasse, 75015 Paris - France)
- UPD5 - Université Paris Descartes - Paris 5 : UMR_S 1163 (12, rue de l'École de Médecine - 75270 Paris cedex 06 - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U1163 (101, rue de Tolbiac, 75013 Paris - France)
11
Newcastle Upon Tyne Hospitals NHS Foundation Trust (Queen Victoria Road, Newcastle upon Tyne, NE1 4LP - United Kingdom)
12
UPD5 - Université Paris Descartes - Paris 5 (12, rue de l'École de Médecine - 75270 Paris cedex 06 - France)
13
University of Edinburgh (Old College South Bridge Edinburgh EH8 9YL - United Kingdom)
Abstract : Excessive type I interferon (IFNα/β) activity is implicated in a spectrum of human disease, yet its direct role remains to be conclusively proven. We investigated two siblings with severe early-onset autoinflammatory disease and an elevated IFN signature. Whole-exome sequencing revealed a shared homozygous missense Arg148Trp variant in STAT2, a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing STAT2R148W in homozygosity (but not heterozygosity) were hypersensitive to IFNα/β, which manifest as prolonged Janus kinase-signal transducers and activators of transcription (STAT) signaling and transcriptional activation. We show that this gain of IFN activity results from the failure of mutant STAT2R148W to interact with ubiquitin-specific protease 18, a key STAT2-dependent negative regulator of IFNα/β signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFNα/β signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFNα/β activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.
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Journal articles
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https://hal-pasteur.archives-ouvertes.fr/pasteur-02430168
Contributor : Marie-Christine Vougny <>
Submitted on : Tuesday, January 7, 2020 - 10:36:53 AM
Last modification on : Wednesday, July 21, 2021 - 4:10:02 PM
Contributor : Marie-Christine Vougny <>
Submitted on : Tuesday, January 7, 2020 - 10:36:53 AM
Last modification on : Wednesday, July 21, 2021 - 4:10:02 PM
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- HAL Id : pasteur-02430168, version 1
- DOI : 10.1126/sciimmunol.aav7501
- PUBMED : 31836668
Collections
PASTEUR | UNIV-PARIS5 | USPC | UNIV-PARIS | UP-SANTE
Citation
Christopher Duncan, Benjamin Thompson, Rui Chen, Gillian Rice, Florian Gothe, et al.. Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2. Science Immunology, American Association for the Advancement of Science, 2019, 4 (42), pp.eaav7501. ⟨10.1126/sciimmunol.aav7501⟩. ⟨pasteur-02430168⟩
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